tbuckley/cabot-search huggingface dataset:
Preclinical evaluation of novel HER3-targeting radioconjugates for the imaging and treatment of HER3-expressing cancers.
Authors: Denis Beckford Vera, Jason Li, Le-Cun Xu, Debbie Lewis, Amanda Chin, Patrik Brodin, Mary Chen, Monideepa Roy, Helen Kotanides
Journal: Journal of Clinical Oncology (2023)

e15114 Background: HER3 overexpression in tumors is associated with poor survival and is implicated in drug resistance mechanisms of HER1 (EGFR) and HER2 targeted therapies. Although antibodies against HER3 have been developed and evaluated in clinical trials, no HER3 targeted therapy has been approved, underscoring the unmet need for novel HER3 therapeutic approaches. We hypothesized that HER3 radioligand targeted therapies could provide enhanced therapeutic efficacy against HER3-positive cancers through the energy deposited by alpha or beta emitting radionuclides in tumor cells. Here we describe the development and preclinical evaluation of novel anti-HER3 antibody radioconjugates (ARCs), 225 Ac-HER3 and 177 Lu-HER3, using the alpha-emitting Actinium-225 ( 225 Ac) and beta-emitting Lutetium-177 ( 177 Lu) radioisotopes, respectively. Methods: ARCs were prepared by radiolabeling HER3 antibody with 225 Ac or 177 Lu using S-2-(4-Isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (p-SCN-Bn-DOTA) to yield 225 Ac or 177 Lu-HER3-ARCs. DOTA modified antibodies were characterized by HPLC and MALDI-TOF and HER3-ARCs were fully characterized by instant thin-layer chromatography (iTLC) and HPLC. The in vitro binding properties of the HER3-ARCs were evaluated using HER3 recombinant proteins and cells expressing HER3 in ELISA and flow cytometry. The in vivo pharmacological properties of the HER3-ARCs were evaluated by molecular imaging using Zirconium-89 ( 89 Zr) Positron Emission Tomography (PET), biodistribution and antitumor efficacy studies. Results: HER3 antibody was successfully modified with p-SCN-Bn-DOTA to yield a conjugate with approximately 8 DOTAs per antibody molecule. Results from the in vitro binding assays of ARCs to either HER3 human recombinant protein or cells expressing HER3 demonstrated similar binding properties of 225 Ac-HER3 and 177 Lu-HER3 to unmodified HER3 antibody. The biodistribution study in NCI-H1975 tumor bearing mice showed that both 225 Ac-HER3 and 177 Lu-HER3-ARCs specifically accumulate in HER3-expressing tumors relative to other tissues. In agreement with the biodistribution studies, PET images revealed specific uptake of 89 Zr-HER3 in NCI-H1975 tumors. Furthermore, 225 Ac and 177 Lu-HER3-ARCs showed significantly more potent NCI-H1975 tumor growth inhibition compared to controls. Conclusions: Our findings suggest that a HER3 targeted radiotherapy approach can enhance therapeutic response and overcome the limitations of previously explored HER3 targeted drug modalities. Thus, further preclinical evaluation of 225 Ac-HER3 and 177 Lu-HER3 is warranted, including in settings of tumor drug resistance, which can provide the basis for investigating HER3-ARCs as an effective treatment approach in future clinical trials.
A multi-component educational intervention for oncologists to improve tobacco cessation treatment among patients with cancer who smoke.
Authors: Thulasee Jose, Joshua Ohde, David O Warner
Journal: Journal of Clinical Oncology (2023)

e22500 Background: Oncologists are change agents to improve tobacco cessation among patients. As part of the National Cancer Institute Cancer Center Cessation Initiative, we established an electronic health record (EHR, Epic)-based "opt-out" approach to refer patients to tobacco treatment specialist without active involvement by oncologists. However, the role of oncologists in contributing to the “opt-out” approach to patients has not been explored. We tested the hypothesis that a multi-component educational program for oncologists would increase the proportion of patients who completed tobacco treatment appointments. Methods: As a quality improvement initiative, oncology providers at the Rochester Mayo Clinic Cancer Center were educated using a multimodal academic detailing approach with group and individual educational sessions. Its effectiveness was tested using a modified step-wedge implementation design. The primary outcomes were patient behaviors that could plausibly be changed by conversations with their provider: the rate at which cancer patients identified as current tobacco users scheduled an appointment in the Nicotine Dependence Center (NDC) (which required active patient involvement), and the rate at which patients scheduled for a NDC appointment completed their appointment. Comparisons were made before, during, and after the education period (from July through Dec 2019) and with a separate group of providers who did not complete education (results examined over a similar time period). Results: Education did not improve outcomes in providers who received education; indeed, the rate of appointment scheduling decreased, although this may reflect other concurrent changes in the referral process (Table). Outcomes were similar between providers who did and did not receive education. Conclusions: Tobacco cessation efforts should be routinely integrated into cancer care to improve outcomes. The “opt-out” program resulted in approximately 1 in 5 cancer patients being seen for tobacco use, but an academic detailing approach designed to equip oncology providers to encourage their patients to complete appointments was not effective. Other approaches are needed to increase the uptake of tobacco treatment in these patients. [Table: see text]
Cemiplimab in first line treatment for locally advanced and metastatic skin squamous cell carcinoma in Slovenia.
Authors: Janja Ocvirk, Masa Sever, Blaz Tomic, Tanja Mesti
Journal: Journal of Clinical Oncology (2023)

e21531 Background: Cemiplimab is a first PD1 inhibitor for treatment of locally advanced cutaneous squamous cell carcinoma (laSCC) and metastatic SCC (mSCC). The purpose of this study is to report outcomes of patients with SCC, treated with cemiplimab in routine clinical practice in Slovenia in twenty-month period. Methods: In this retrospective cohort study we analyzed medical records of patients with laSCC and mSCC inappropriate for surgery or radiotherapy treated with cemiplimab in first line between May 2020 and November 2022. The baseline characteristics, outcomes, immune related adverse events (irAE). Results: 28 patients were included, 24 with laSCC and 4 with mSCC, with a median age of 76.1 years. Of them, 18 % (5 patients) a concomitant autoimmune disease. The estimated median progression-free survival (PFS) was 4.4 months (95% CI: 1.5–7.3). The median overall survival (OS) was 7.3 months (95% CI: 4.6–9.9). Among 27 treated patients with an evaluable response, 3 (11 %) achieved complete response, 5 (19 %) achieved partial response, 6 (22 %) had stable disease and 13 (48 %) patients experienced a progressive disease. The overall response rate (ORR) was 30 %, and the disease control rate (DCR) was 52 %. A quarter of all patients had at least one immune related adverse events (irAEs). Only one patient had grade 3 event, there were no grade 4 and no fatal events. Higher response rate was achieved in patients with irAE – ORR was 43 % and DCR was 71 %. Seven patients are still on cemiplimab. Conclusions: Cemiplimab has shown meaningful efficacy with DCR of 52 % in patients with laSCC and mSCC in Slovenia. Patients developing irAE had higher response rate.
Preclinical antitumor activity of an anti-HER2/Trop-2 bispecific antibody-drug conjugate with a new DNA topoisomerase I inhibitor.
Authors: Helen Zhong, Yan Xiong, Han Huang, Yuming Pan, Lijin Cao, Shen Liu, Na Wang, Bing Sun, Dingguo Liu, Wei Yuan, Jan Fang, Haifeng Bao
Journal: Journal of Clinical Oncology (2023)

e15013 Background: In recent years, antibody-drug conjugates (ADCs) have made significant progress in cancer therapy and show a promising future. Among the approved ADCs, Enhertu, the HER2 directed ADC and Trodelvy, the Trop-2 directed ADC, have shown considerable clinical benefits. Bispecific antibody-drug conjugate represents a fast-growing class of next generation ADC due to its potentials in enhancing specificity, improving efficacy, and reducing toxicity. Additionally, targeting more than one molecule can be useful to avoid resistance to treatment and broaden the patient population. Methods: We generated a novel bispecific ADC (BIO-201) co-targeting HER2 and Trop-2 which are the two clinically validated tumor-associated antigens that are expressed on a wide variety of tumors. BIO-201 is consisted of a novel bispecific anti-HER2/Trop-2 antibody conjugated with a potent DNA topoisomerase I inhibitor (TOPO Ii) via a cleavable linker. TOPO Ii is a proprietary payload platform developed in house that exhibits similar characteristics including in vitro and in vivo anti-tumor activities and safety profile to DXd. The bispecific antibody was fully characterized and in vitro and in vivo anti-tumor activity of BIO-201 was assessed using preclinical models. Results: The bispecific antibody showed comparable or increased cell binding and internalization compared with the parental antibodies in various tumor cells that express different surface levels of HER2 and Trop-2. In the in vitro cytotoxicity assay, the bispecific ADC BIO-201 effectively killed cancer cells with IC50 in the sub nM range with BIO-201 being most potent against cancer cells that co-express HER2 and Trop-2. The anti-tumor activity of BIO-201 was further demonstrated in vivo in several tumor xenograft models. Treatment of BIO-201 induced significant tumor regression in HER2 or Trop-2 positive tumors, suggesting broader coverage of tumor types than conventional HER2 and Trop-2 ADCs. BIO-201 also showed similar anti-tumor activity to Herceptin-DXd. Conclusions: Taken together, these findings suggest that anti-HER2/Trop-2 bispecific ADC has potential as an effective therapy for a variety of cancers that co-express HER2/Trop-2 or express either of the targets. BIO-201 may be expected to have a similar clinical activity to Enhertu or Trodelvy but treat more patient sub-populations and indications.
Sex differences in cancer incidence rates by race and ethnicity: Results from the surveillance, epidemiology, and end results (SEER) Registry (2000-2019).
Authors: Sararat Tosakoon, Wayne R. Lawrence, Meredith S. Shiels, Sarah S. Jackson
Journal: Journal of Clinical Oncology (2023)

10547 Background: Sex differences in cancer incidence are pronounced, with men having 2-3 times the rate of most non-reproductive cancers than women. However, whether the male predominance is due to differences in biological factors or behavior remains not well understood. This study investigated sex differences in cancer incidence by race and ethnicity to provide a greater understanding of whether differences are driven by biological factors or environmental exposures. Methods: Cancer incidence data from the Surveillance, Epidemiology and End Result (SEER) program (2000-2019) was used to calculate male-to-female incidence rate ratios (MF IRR) for each cancer site and histological subtype, stratified by race and ethnicity (non-Hispanic White, non-Hispanic Black, non-Hispanic Asian/Pacific Islander, American Indian/Alaskan Native, and Hispanic), and age-standardized to the 2000 U.S. population for individuals ages ≥20 years. Results: Most non-reproductive cancers had a male predominance across race and ethnicity, with the largest MF IRR seen for cancers of the tonsil, hypopharynx, larynx, and Kaposi sarcoma (MF IRR &gt; 4). Three cancers, gallbladder; peritoneum, omentum, mesenter; and thyroid, were more common among females than males across all race and ethnicity. Females had a higher incidence of anal cancer than males for all racial and ethnic groups except for non-Hispanic Black individuals where the MF IRR was &gt;1. Cancers of the stomach, skin (excluding basal and squamous cell), melanoma skin, and other non-epithelial, and myeloma had greater MF IRR among non-Hispanic White adults than all other racial and ethnic groups. Non-Hispanic Black individuals had higher MF IRR of cancers of the liver and lung and bronchus, compared to other racial and ethnic group. Non-Hispanic White males had the highest MF IRRs for esophagus adenocarcinoma and gastric cardia adenocarcinoma and the lowest MF IRR for esophagus SCC compared to other races and ethnicity. Conclusions: The MF IRR for most cancers in this study did not differ by race and ethnicity, suggesting the influence of biological factors. Differences in the MF IRR across race and ethnicity may indicate carcinogenic exposure differences leading to the development of non-sex-specific cancers. Further research is needed to identify biological drivers of cancer incidence for most non-reproductive cancers. Funding: Intramural Research Program of the Division of Cancer Epidemiology and Genetics in the National Cancer Institute, National Institutes of Health.
The impact of renin-angiotensin-aldosterone system inhibitors on immune checkpoint inhibitor-associated adverse cardiovascular events.
Authors: Cho Hung Chiang, Cho Han Chiang, YUANPING HSIA, Cho Hsien Chiang, Her-Shyong Shiah
Journal: Journal of Clinical Oncology (2023)

2605 Background: Immune checkpoint inhibitors (ICIs) are associated with adverse cardiovascular events that impair patient outcomes. Previous observational studies showed that renin-angiotensin-aldosterone system inhibitors (RAASi) may mitigate the cardiotoxicity associated with chemotherapeutic agents. However, the effects of RAASi on ICI-associated adverse cardiovascular events are unknown. Methods: We conducted a 1:1 propensity score-matched cohort study involving ICI-treated patients at two tertiary referral centers in Taiwan. The propensity score matching model includes age, sex, hypertension, diabetes mellitus, chronic kidney disease, Eastern Cooperative Oncology Group (ECOG) Performance Scale, cancer stage, and cancer type. The primary outcome was major adverse cardiovascular events (MACE), defined as a composite of myocardial infarction (MI), ischemic stroke, peripheral arterial occlusive disease (PAOD), pulmonary embolism (PE), deep venous thrombosis (DVT), heart failure, pericardial disease, myocarditis, and cardiac arrhythmias. The secondary outcomes were arterial thrombotic events (MI, ischemic stroke, PAOD) and venous thrombotic events (PE and DVT). Results: We identified 684 patients eligible for inclusion, from which 164 patients who received RAASi were matched to patients who did not receive RAASi. Over a median follow-up of 9.1 months, the incidence rate of MACE for RAASi and non-RAASi recipients was 6.5 and 13.9 per 100 patient-years, respectively, resulting in an incidence rate ratio of 0.47 [95% CI: 0.21–1.00] (p = 0.038). In a multivariate Cox proportional hazard model adjusting for cancer therapy, RAASi recipients had an approximately 60% reduction in the risk for MACE (HR, 0.37 [95% CI: 0.16-0.86], p = 0.021). In the secondary analysis, RAASi were associated with a reduction in venous thrombotic events (HR, 0.11 [95% CI: 0.02-0.63], p = 0.013), but not for arterial thrombotic events (HR, 0.47 [95% CI: 0.06-3.38], p = 0.45). Conclusions: In patients receiving ICI therapy, the use of RAASi is associated with a decreased cardiovascular risk, particularly for venous thrombotic events. [Table: see text]
Outcomes by occurrence of immune-mediated adverse events (imAEs) with tremelimumab (T) plus durvalumab (D) in the phase 3 HIMALAYA study in unresectable hepatocellular carcinoma (uHCC).
Authors: George Lau, Ann-Lii Cheng, Bruno Sangro, Masatoshi Kudo, Robin Kate Kelley, Won Young Tak, Antonio Gasbarrini, Maria Reig, Ho Yeong Lim, David Tougeron, Enrico N. De Toni, Vincent C. Tam, Kabir Mody, Jun Gong, Carrie L. McCoy, Charu Gupta, Mallory Makowsky, Alejandra Negro, Ghassan K. Abou-Alfa
Journal: Journal of Clinical Oncology (2023)

4004 Background: Immune checkpoint inhibitor (ICI) studies have shown an association between the occurrence of imAEs and outcomes. In the Phase 3 HIMALAYA study (NCT03298451) in uHCC, STRIDE (Single T Regular Interval D) significantly improved overall survival (OS) vs sorafenib (S), and D monotherapy was noninferior to S. STRIDE and D had manageable safety (Abou-Alfa et al. NEJM Evid 2022). STRIDE is approved for uHCC in the United States and Japan and recommended for approval by the European Medicines Agency; D is approved in Japan. This exploratory analysis assessed the association between imAEs and outcomes in HIMALAYA. Methods: Safety was assessed in participants (pts) who received ≥1 dose of STRIDE (T 300 mg [one dose] plus D 1500 mg once every 4 weeks [Q4W]) or D (1500 mg Q4W). imAEs were AEs of special interest associated with drug exposure and consistent with an immune-mediated mechanism of action with no found alternate etiology. Median OS (mOS) and OS rates were estimated using the Kaplan–Meier method. OS hazard ratios (HRs) and 95% CIs were calculated using Cox modeling, with imAEs as a time-varying covariate and stratified by etiology (HBV/HCV/others), ECOG (0/1), and macro-vascular invasion (yes/no) for pts with vs without imAEs of any grade. Pts with &gt;1 imAE were counted once. Results: In total, 388 pts (STRIDE) and 388 pts (D) were included in the analysis. Any grade imAEs, Grade 3 or 4 imAEs, and imAEs leading to discontinuation occurred in 139 (35.8%), 49 (12.6%), and 22 (5.7%) pts, respectively for STRIDE and 64 (16.5%), 25 (6.4%), and 10 (2.6%) pts, respectively for D. imAEs requiring high-dose steroids (≥40 mg prednisone or equivalent daily) occurred in 78 (20.1%) pts for STRIDE and 37 (9.5%) pts for D. An improvement in OS was seen with STRIDE in pts with imAEs vs pts without (HR, 0.73; 95% CI, 0.56–0.95). OS rates at 6, 12, and 24 months (mo) were higher for STRIDE in pts with imAEs vs pts without. The association between imAEs and OS was less clear for D and may be limited by small pt number. In a landmark analysis of pts with vs without imAEs within 6 mo of STRIDE (n=307) or D (n=287), OS HRs (95% CIs) were 0.65 (0.47–0.90) and 1.39 (0.95–2.04), respectively. Conclusions: In HIMALAYA, imAEs with STRIDE or D were manageable and generally low grade. In this exploratory analysis, the occurrence of imAEs was associated with improved OS for STRIDE, generally consistent with findings for other ICIs. Clinical trial information: NCT03298451 . [Table: see text]
Association of circulating CD103<sup>+</sup> T cells with major pathological response in a randomized phase 2 trial of neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non-small cell lung cancer.
Authors: Zachary Walsh, Johannes C Melms, Meri Rogava, Lindsay Caprio, Casey Ager, Amit Dipak Amin, Patricia Ho, Murtaza Malbari, Vivek Mittal, Timothy McGraw, Nasser K. Altorki, Benjamin Izar
Journal: Journal of Clinical Oncology (2023)

8550 Background: We previously reported results of a randomized phase 2 study, demonstrating a higher rate of major pathological response to durvalumab in combination with stereotactic body radiotherapy (SBRT) compared to durvalumab alone in patients with localized (stage I-IIIA) non-small cell lung cancer (NSCLC). Biomarkers of response in NSCLC are poorly understood. To address this, we evaluated sequentially collected peripheral blood mononuclear cells (PBMCs) from study participants to identify easily accessible biomarkers associated with major pathological responses. Methods: PBMCs were obtained from study participants at defined pre-treatment, peri-operative, and post-operative timepoints. We performed 25-marker spectral flow cytometric analysis of the T cell compartment in these samples and used dimensionality reduction and clustering programs to identify populations of interest. Results: Our analysis of these samples revealed populations of both CD4 + and CD8 + T cells with hallmarks of prior antigen exposure and tissue residency (CD103 + , CCR7 - , CD45RA - ), suggesting tumor-experienced T cells circulating into the blood. Greater pre-treatment frequency of these T cell populations was associated with major pathological responses to neoadjuvant therapy. This observation was consistent when evaluating patients with major pathological responses across both treatment arms, and within the durvalumab plus SBRT group, where we had enough patients with major pathological responses. Maturation of disease-free survival data from this trial will enable us to evaluate the association of these biomarkers with long-term survival. Conclusions: Together, these data reveal an unexpected population of T cells in the peripheral blood with features of tissue-residency, which are associated with major pathological responses, and suggest that re-circulation of tumor-experienced T cells may represent a predictive biomarker for neoadjuvant treatment of NSCLC.
Intratumoral heterogeneity as a predictive biomarker in immunotherapy for advanced esophageal cancer.
Authors: Jingde Chen, Yanan Hai, Wenfang Bao, Chen Chen
Journal: Journal of Clinical Oncology (2023)

e16059 Background: Previous studies have shown that the acquired resistance to anti-cancer therapy is largely due to intratumoral heterogeneity (ITH), thus leading to unfavourable prognosis. As known, there is no comprehensive research using ITH as a biomarker to predict the efficacy of immunotherapy in advanced esophageal cancer (ESCA) patients. Methods: Bioconductor R package Maftools was used to analyze somatic variants of advanced ESCA from MSK-IMPACT-1611 study cohort (PMID: 30643254) with data from 39 patients. We then used a mutant-allele tumor heterogeneity (MATH) algorithm to measure ITH score and analyzed the difference in the genetic profile between the ITH score high (ITH-H) and ITH score low (ITH-L) groups, the association with tumor mutational burden (TMB), and the effect of ITH on the prognosis of immunotherapy. Results: There were significant differences in gene mutation spectrum between ITH-H and ITH-L groups. The genes with the highest mutation frequency in ITH-H group were TP53 (93.75%), CDKN2A (37.5%), PREX2 (31.25%), PTPRD (25%), ALK (18.75%), ERBB4 (18.75%), and KMT2D (18.75%), while the genes with the highest mutation frequency in ITH-L group were TP53 (69.57%), CDKN2A (21.74%), PIK3CA (21.74%), APC (17.39%), ARID1A (17.39%), LATS1 (17.39%), and RNF43 (17.39%).There was significant difference in median overall survival (mOS) between ITH-L and ITH-H groups (not reach versus 5 months, hazard ratio (HR) = 3.96, 95%CI 1.02−15.39, P = 0.034). There was no significant difference in median TMB levels between ITH-L and ITH-H groups (7 Muts/Mb versus 8 Muts/Mb, P = 0.09). The TMB high (TMB-H) patients had no significantly better mOS than the TMB low (TMB-L) group (HR = 0.27, 95%CI 0.06−1.26, P = 0.072). A pooled analysis of ITH and TMB show that mOS in the ITH-L+ TMB-H group was significantly better than that in the ITH-L+TMB-L, ITH-H+TMB-H, and ITH-H+TMB-L group (HR = 2.03, 95%CI 0.06−7.69, P = 0.002). Conclusions: The results suggest ITH is a predictor of ESCA immunotherapy efficacy independent of TMB.